Variants of the IFI16 gene affecting the levels of expression of mRNA are associated with susceptibility to Behçet disease.
Behçet disease (BD) is a multifactorial disease in which infectious agents have been proposed as triggers in genetically predisposed individuals. The aim of our study was to investigate the role of innate immunity receptors, specifically the nucleic acid sensors, in susceptibility to BD. Seventy-four tag single nucleotide polymorphisms (tSNP) selected in 9 candidate genes (DDX58, IFIH1, TLR3, TLR7, TLR8, AIM2, IFI16, ZBP1, and TLR9) were genotyped in 371 patients and 854 controls. Assays of mRNA expression and allele-specific transcript quantification (ASTQ) were performed in 110 and 50 controls, respectively. Patients and controls were genotyped and 2 tSNP (rs6940 in IFI16 and rs855873 in AIM2) were associated with BD. To confirm this association, these tSNP were genotyped in 850 additional controls, and the total cohort was randomly divided into 2 cohorts. The association of these 2 tSNP with the disease remained in both cohorts. One haplotype (rs6940T-rs855873G) was identified as a risk factor (OR 1.41, 95% CI 1.06-1.86, p = 0.015), and another (rs6940A-rs855873A) as a protective factor (OR 0.65, 95% CI 0.47-0.90, p = 0.009). Samples with the risk haplotype had lower IFI16 expression levels than samples with the protective (0.99 ± 0.29 vs 1.23 ± 0.50, p = 0.022). Consistently, in the ASTQ assays performed with the nonsynonymous rs6940 SNP, the risk allele had lower IFI16 expression levels than the protective (p = 0.027). Our findings suggest association of IFI16, a cytosolic sensor of dsDNA and mediator of the AIM2 inflammasome-dependent pathway, in susceptibility to BD. Differences genetically determined in the levels of this molecule could be the cause of this association.


Retrospective validation of a machine learning clinical decision support tool for myocardial infarction risk stratification.
Diagnosis and appropriate intervention for myocardial infarction (MI) are time-sensitive but rely on clinical measures that can be progressive and initially inconclusive, underscoring the need for an accurate and early predictor of MI to support diagnostic and clinical management decisions. The objective of this study was to develop a machine learning algorithm (MLA) to predict MI diagnosis based on electronic health record data (EHR) readily available during Emergency Department assessment. An MLA was developed using retrospective patient data. The MLA used patient data as they became available in the first 3 h of care to predict MI diagnosis (defined by International Classification of Diseases, 10th revision code) at any time during the encounter. The MLA obtained an area under the receiver operating characteristic curve of 0.87, sensitivity of 87% and specificity of 70%, outperforming the comparator scoring systems TIMI and GRACE on all metrics. An MLA can synthesize complex EHR data to serve as a clinically relevant risk stratification tool for MI.


Optimization of breeding program design through stochastic simulation with kernel regression.
In recent years, breeding programs have increased significantly in size and complexity, with various highly interdependent parameters and many contrasting breeding goals. As a result, resource allocation in these programs has become more complex, and deriving an optimal breeding strategy has become increasingly challenging. To address this, a common practice is to reduce the optimization problem to a set of scenarios that differ only in a few parameters and can therefore be analyzed in detail. The goal of this article is to provide a framework for the numerical optimization of breeding programs that goes beyond the simple comparison of scenarios. For this, we first determine the space of potential breeding programs only limited by basic constraints like the budget and housing capacities. Subsequently, the goal is to identify the optimal breeding program by finding the parametrization that maximizes the target function by combining different breeding goals. To assess the value of the target function for a parametrization, we propose using stochastic simulations and the subsequent use of a kernel regression method to cope with the stochasticity of simulation outcomes. This procedure is performed iteratively to narrow down the most promising areas of the search space and perform more and more simulations in these areas of interest. In a simplified example applied to a dairy cattle program, our proposed framework has shown its ability to identify an optimal breeding strategy that aligns with a target function aiming at genetic gain and genetic diversity conservation limited by budget constraints.


Encoding pitch contours using current steering.
This study investigated cochlear implant (CI) users' ability to perceive pitch cues from time-varying virtual channels (VCs) to identify pitch contours. Seven CI users were tested on apical, medial, and basal electrode pairs with stimulus durations from 100 to 1000 ms. In one stimulus set, 9 pitch contours were created by steering current between the component electrodes and the VC halfway between the electrodes. Another stimulus set only contained 3 pitch contours (flat, falling, and rising). VC discrimination was also tested on the same electrodes. The total current level of dual-electrode stimuli was linearly interpolated between those of single-electrode stimuli to minimize loudness changes. The results showed that pitch contour identification (PCI) scores were similar across electrode locations, and significantly improved at longer durations. For durations longer than 300 ms, 2 subjects had nearly perfect 9-contour identification, and 5 subjects perfectly identified the 3 basic contours. Both PCI and VC discrimination varied greatly across subjects. Cumulative d(') values for VC discrimination were significantly correlated with 100-, 200-, and 500-ms PCI scores. These results verify the feasibility of encoding pitch contours using current steering, and suggest that identification of such pitch contours strongly relies on CI users' sensitivity to VCs.


Immortalization of human oral keratinocytes is associated with elevation of telomerase activity and shortening of telomere length.
Telomerase is a ribonucleoprotein complex that synthesizes TTAGGG repeat sequences at the ends of mammalian chromosomes. Its activity is found in most cancer cells and few rare normal somatic cells. To investigate whether telomerase activity and telomere length of normal human oral keratinocytes (NHOK) are altered by <high risk> human papillomaviruses (HPV), we transfected primary NHOK with type 16 HPV (HPV-16) genome and determined the activity of telomerase. HPV transfection extended the life span of NHOK and eventually induced immortalization of cells. Moderate telomerase activity was consistently observed in rapidly proliferating NHOK, and activity was not changed in HPV-16 transfected cells with extended life span. However, the activity was sharply increased when cells passed the crisis stage. Telomere length, which remained constant at approximately 6.8 kb during serial passages of NHOK, progressively shortened in HPV DNA transfected cells during the period of extended life span and continued until crisis, after which it stabilized at approximately 5 kb. These results demonstrate that immortalization of NHOK with HPV-16 DNA is associated with the activation of telomerase.


Adenomyosis: Back to the future?
Adenomyosis is a benign invasion of endometrium into the myometrium. It produces a diffusely enlarged uterus and predominantly affects women in the late reproductive age. It has recently been associated with a negative impact on female fertility. Diagnosis is challenging because nonspecific symptoms can be present. However, it is asymptomatic in the majority of women. Medical treatment with GnRH agonist seems to be promising, particularly in subfertile women. A retrospective study was performed (182 patients) by examination of histopathological results with "adenomyosis" between January/2013 and September/2016. The patients ranged in age from 34 to 78 years and the majority (94.5%) were over 40 years old. Most (90.6%) were multiparous. All women underwent a sonographic evaluation. More than a half had a heterogeneous myometrium (75.7%) and concomitant presence of myoma (65.4%). The majority of women were asymptomatic, nevertheless, when symptoms were present, menorrhagia and metrorrhagia were the most important complaints. About one third of women had had prior uterine surgery, 67.6% had had previous caesarean section(s). Medical treatment with progestatives was used by 61.3% of women and 23% tried more than one type of hormone therapy. Endometrial cancer was present in 5.5% of cases, all of which were lowgrade endometrioid adenocarcinoma. Adenomyosis is an important challenge in gynaecology and often remains a post-operative diagnosis after hysterectomy. Clinicians should be on the watch for ultrasound features suggesting its presence to allow an early diagnosis. Future investments in the creation of diagnostic algorithms and alternative treatments are warranted.


Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR.
RNA processing is critical for proper spatial and temporal control of gene expression. The ubiquitous nuclear polyadenosine RNA binding protein, PABPN1, post-transcriptionally regulates multiple steps of gene expression. Mutations in the PABPN1 gene expanding an N-terminal alanine tract in the PABPN1 protein from 10 alanines to 11-18 alanines cause the muscle-specific disease oculopharyngeal muscular dystrophy (OPMD), which affects eyelid, pharynx, and proximal limb muscles. Previous work revealed that the Pabpn1 transcript is unstable, contributing to low steady-state Pabpn1 mRNA and protein levels in vivo, specifically in skeletal muscle, with even lower levels in muscles affected in OPMD. Thus, low levels of PABPN1 protein could predispose specific tissues to pathology in OPMD. However, no studies have defined the mechanisms that regulate Pabpn1 expression. Here, we define multiple cis-regulatory elements and a trans-acting factor, HuR, which regulate Pabpn1 expression specifically in mature muscle in vitro and in vivo. We exploit multiple models including C2C12 myotubes, primary muscle cells, and mice to determine that HuR decreases Pabpn1 expression. Overall, we have uncovered a mechanism in mature muscle that negatively regulates Pabpn1 expression in vitro and in vivo, which could provide insight to future studies investigating therapeutic strategies for OPMD treatment.


Diagnosis and management of cryptococcal meningitis in HIV-infected adults.
SUMMARYCryptococcal meningitis is a leading cause of morbidity and mortality globally, especially in people with advanced HIV disease. Cryptococcal meningitis is responsible for nearly 20% of all deaths related to advanced HIV disease, with the burden of disease predominantly experienced by people in resource-limited countries. Major advancements in diagnostics have introduced low-cost, easy-to-use antigen tests with remarkably high sensitivity and specificity. These tests have led to improved diagnostic accuracy and are essential for screening campaigns to reduce the burden of cryptococcosis. In the last 5 years, several high-quality, multisite clinical trials have led to innovations in therapeutics that have allowed for simplified regimens, which are better tolerated and result in less intensive monitoring and management of medication adverse effects. One trial found that a shorter, 7-day course of deoxycholate amphotericin B is as effective as the longer 14-day course and that flucytosine is an essential partner drug for reducing mortality in the acute phase of disease. Single-dose liposomal amphotericin B has also been found to be as effective as a 7-day course of deoxycholate amphotericin B. These findings have allowed for simpler and safer treatment regimens that also reduce the burden on the healthcare system. This review provides a detailed discussion of the latest evidence guiding the clinical management and special circumstances that make cryptococcal meningitis uniquely difficult to treat.


Tracking adhesion factors in Staphylococcus caprae strains responsible for human bone infections following implantation of orthopaedic material.
Ten Staphylococcus caprae strains isolated from four patients and responsible for bone infections following implantation of orthopaedic material were compared to four S. caprae strains collected from milk samples of healthy goats. The following characteristics were investigated: Smal patterns, hybridization patterns with pBA2 (ribotypes), slime production, adhesion to matrix proteins (fibrinogen, fibronectin, collagen) and the staphylococcal adhesion genes (fnbA, clfA, cna, atlE, ica, fbe). None of the characteristics enabled us to distinguish the human strains from the goat strains. Slime was occasionally produced by S. caprae strains but all of them carried nucleotide sequences hybridizing at low stringency with the following genes: atlE encoding a S. epidermidis autolysin binding vitronectin and responsible for the primary adhesion to polystyrene, ica operon involved in the biosynthesis of a S. epidermidis extracellular polysaccharide, and the part of clfA encoding the serine-aspartate repeated region of a S. aureus cell-wall fibrinogen-binding protein.


Queuing Network Modeling of Driver EEG Signals-Based Steering Control.
Directly using brain signals rather than limbs to steer a vehicle may not only help disabled people to control an assistive vehicle, but also provide a complementary means of control for a wider driving community. In this paper, to simulate and predict driver performance in steering a vehicle with brain signals, we propose a driver brain-controlled steering model by combining an extended queuing network-based driver model with a brain-computer interface (BCI) performance model. Experimental results suggest that the proposed driver brain-controlled steering model has performance close to that of real drivers with good performance in brain-controlled driving. The brain-controlled steering model has potential values in helping develop a brain-controlled assistive vehicle. Furthermore, this study provides some insights into the simulation and prediction of the performance of using BCI systems to control other external devices (e.g., mobile robots).


Neuropathy experienced by colorectal cancer patients receiving oxaliplatin: A qualitative study to validate the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale.
Although oxaliplatin is widely established as a standard treatment in colorectal cancer (CRC), oxaliplatin-induced neuropathy has emerged as a prominent dose-limiting side effect associated with quality of life decrements. Ongoing monitoring and management of neuropathy is important for CRC patient quality of life and adherence to treatment. Therefore, a validated self-reported measure of neuropathy would aid in the management and assessment of oxaliplatin-induced neuropathy in clinical practice and research. We sought to evaluate the content validity of the 13-item Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity subscale (FACT/GOG-Ntx) for CRC patients receiving oxaliplatin. To understand the neuropathy experiences of CRC patients and assess content validity of the FACT/GOG-Ntx. Semi-structured concept elicitation and cognitive debriefing interviews were conducted with 31 CRC patients experiencing peripheral neuropathy from current or previous oxaliplatin treatment. Interview data were analyzed using a constant comparative approach, and data were mapped to the FACT/GOG-Ntx to assess content validity. Mean age of the sample was 54 (range 34-82). The sample was primarily Caucasian (84%) and consisted of nearly equal numbers of men and women. Participants described 28 unique neuropathy symptoms; hand tingling (experienced by 87% of respondents); feet tingling (81%); hand numbness (68%); and feet numbness (84%) were most frequently mentioned. Neuropathy symptoms occurring on the feet were most often identified as most bothersome by participants. Eleven of the 13 FACT/GOG-Ntx items exhibited moderate to strong evidence of content validity. Two items related to trouble hearing and ringing in the ears had weak support; however, these items represent severe neuropathy and could be useful for a patient reported outcome measure. The FACT/GOG-Ntx represents the key neuropathy experiences of CRC patients treated with oxaliplatin.


Cognitive and behavioral effects of cannabidiol in patients with treatment-resistant epilepsy.
Therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably over the last ten years. As more evidence for the potentially beneficial effects of CBD on different epilepsy types is emerging, it is important to monitor potential cognitive and behavioral side effects. So far, studies including standardized neuropsychological data in the context of treatment with CBD in epilepsy patients are sparse. The present open-label study examines cognitive and behavioral effects of CBD in children and adults with treatment resistant epilepsy. Thirty-nine patients with treatment-resistant epilepsy completed the study protocol, i.e. they were tested at baseline (T0) and after three months of CBD treatment (T1). Patients completed standardized neuropsychological tests on memory, executive functions and attention if they were capable. For cognitively impaired patients who could not complete cognitive tests, caregiver interviews were conducted and caregiver questionnaires completed. Significant cognitive decline from T0 to T1 was observed on none of the included measures. There was a significant improvement on a measure of selective attention and on a caregiver-rated behavioral measure. More than 89% of all individual test results remained stable or showed reliable improvement from T0 to T1. Cognitive and behavioral changes from T0 to T1 were not significantly correlated with CBD dose. Improvements in short-term/working memory were significantly related to better therapy response. No adverse group-level effects of CBD treatment were detected. On an individual level, most test results remained stable or were improved. Cognitive change was not related to CBD dose. The present results show that, from a cognitive and behavioral point of view, CBD seems to have an encouraging side-effect profile. The results need to be replicated with larger samples.


Lipid rafts alter the stability and activity of the cholera toxin A1 subunit.
Cholera toxin (CT) travels from the cell surface to the endoplasmic reticulum (ER) as an AB holotoxin. ER-specific conditions then promote the dissociation of the catalytic CTA1 subunit from the rest of the toxin. CTA1 is held in a stable conformation by its assembly in the CT holotoxin, but the dissociated CTA1 subunit is an unstable protein that spontaneously assumes a disordered state at physiological temperature. This unfolding event triggers the ER-to-cytosol translocation of CTA1 through the quality control mechanism of ER-associated degradation. The translocated pool of CTA1 must regain a folded, active structure to modify its G protein target which is located in lipid rafts at the cytoplasmic face of the plasma membrane. Here, we report that lipid rafts place disordered CTA1 in a functional conformation. The hydrophobic C-terminal domain of CTA1 is essential for binding to the plasma membrane and lipid rafts. These interactions inhibit the temperature-induced unfolding of CTA1. Moreover, lipid rafts could promote a gain of structure in the disordered, 37 °C conformation of CTA1. This gain of structure corresponded to a gain of function: whereas CTA1 by itself exhibited minimal in vitro activity at 37 °C, exposure to lipid rafts resulted in substantial toxin activity at 37 °C. In vivo, the disruption of lipid rafts with filipin substantially reduced the activity of cytosolic CTA1. Lipid rafts thus exhibit a chaperone-like function that returns disordered CTA1 to an active state and is required for the optimal in vivo activity of CTA1.


Sensory re-education after free neurovascular toe pulp flap for digital pulp reconstruction.
To evaluate the effectiveness of a sensory re-education (SR) program after free neurovascular toe pulp flap for finger or thumb pulp defect reconstruction. From January 2015 to January 2020, 49 patients with finger or thumb pulp defects treated with free fibular side flaps of the great toe or tibial side flaps of the second toe were recruited. The patients were randomly divided into two groups one month after surgery. The training group received the SR program, and the control group underwent the traditional rehabilitation program. Clinical evaluation included Semmes-Weinstein Monofilament (SWM) tests, static two-point discrimination (2-PD), and sensibility grading, measured at 1, 3, 6, 9, and 12 months postoperatively. A total of 42 patients completed the follow-up, including 22 (16 males) patients in the training group and 20 patients (12 males) in the control group. Compared with 1 month after the operation, significant improvements in sensory recovery were observed at 3, 6, 9, and 12 months postoperatively in both groups. In addition, earlier sensory recovery was seen in the SR group compared to the control group, showing significant differences at 3 and 6 months but not at 9 and 12 months postoperatively. Although SR seemed to accelerate preliminary sensory recovery after free neurovascular toe pulp flaps for digital defect reconstruction, the program should be reconsidered as it offers no significant improvement over the control group at later follow-up stages.


Rural hospital inpatient surgical volume: cutting-edge service or operating on the margin?
Surgical services are an important part of modern health care, but providing them to isolated rural citizens is especially difficult. Public policy initiatives could influence the supply, training, and distribution of surgeons, much as they have for rural primary care providers. However, so little is known about the proper distribution of surgeons, their contribution to rural health care, and the safety of rural surgery that policy cannot be shaped with confidence. This study examined the volume and complexity of inpatient surgery in rural Washington state as a first step toward a better understanding of the current status of rural surgical services. Information about rural surgical providers was obtained through telephone interviews with administrators at Washington's 42 rural hospitals. The Washington State Department of Health's Commission Hospital Abstract Recording System (CHARS) data provided a count of the annual surgical admissions at rural hospitals. Diagnosis-related group (DRG) weights were used to measure complexity of rural surgical cases. Surgical volume varied greatly among hospitals, even among those with a similar mix of surgical providers. Many hospitals provided a limited set of basic surgical services, while some performed more complex procedures. None of these rural hospitals could be considered high volume when compared to volumes at Seattle hospitals or to research reference criteria that have assessed volume-outcome relationships for surgical procedures. Several hospitals had very low volumes for some complex procedures, raising a question about the safety of performing them. The leaders of small rural hospitals must recognize not only the fiscal and service benefits of surgical services--and these are considerable--but also the potentially adverse effect of low surgical volume on patient outcomes. Policies that encourage the proper training and distribution of surgeons, the retention of basic rural surgical services, and the rational regionalization of complex surgery are likely to enhance the convenience and safety of surgery for rural citizens.


Low-grade Appendiceal Mucinous Neoplasm and Endometriosis: Incidental Coincident Pathologies at Cesarean Section.
Incidental pathologic findings at the time of Cesarean section are exceedingly uncommon. Similarly, occult low-grade appendiceal mucinous neoplasms and other noninflammatory, non-neoplastic appendiceal pathologies are rare, although appendiceal neoplasia, most commonly well-differentiated neuroendocrine tumors, may be found during evaluation of acute appendicitis. Here we report the first case of incidental coincident low-grade appendiceal mucinous tumor and endometriosis involving the appendix at the time of Cesarean section. We highlight pitfalls in the histopathologic evaluation of these processes, particularly given the setting of decidualization of ectopic endometrial stroma, as well as the prognostic implications of low-grade appendiceal mucinous tumors to emphasize the importance of clinicopathologic correlation and careful intraoperative examination of the appendix and other visible structures during Cesarean section.


Different portions of the maize root system host Burkholderia cepacia populations with different degrees of genetic polymorphism.
In order to acquire a better understanding of the spatial and temporal variations of genetic diversity of Burkholderia cepacia populations in the rhizosphere of Zea mays, 161 strains were isolated from three portions of the maize root system at different soil depths and at three distinct plant growth stages. The genetic diversity among B. cepacia isolates was analysed by means of the random amplified polymorphic DNA (RAPD) technique. A number of diversity indices (richness, Shannon diversity, evenness and mean genetic distance) were calculated for each bacterial population isolated from the different root system portions. Moreover, the analysis of molecular variance (AMOVA) method was applied to estimate the genetic differences among the various bacterial populations. Our results showed that, in young plants, B. cepacia colonized preferentially the upper part of the root system, whereas in mature plants, B. cepacia was mostly recovered from the terminal part of the root system. This uneven distribution of B. cepacia cells among different root system portions partially reflected marked genetic differences among the B. cepacia populations isolated along maize roots on three distinct sampling occasions. In fact, all the diversity indices calculated indicated that genetic diversity increased during plant development and that the highest diversity values were found in mature maize plants, in particular in the middle and terminal portions of the root system. Moreover, the analysis of RAPD patterns by means of the AMOVA method revealed highly significant divergences in the degree of genetic polymorphism among the various B. cepacia populations.


A Simplified Ultrasonographic Score for the Prediction of Cytologically Suspicious Thyroid Nodules.
The major aim of ultrasound (US)-based risk stratification systems is to reduce unnecessary thyroid biopsies without losing the ability to recognize nodules with clinically significant malignancy. Each of the classic suspicious features of a thyroid nodule detected on US scan (hypoechoic pattern, microcalcifications, irregular margin, taller than wide shape, irregular vascularization) is significantly independently associated with the probability of malignancy, but none of them has good diagnostic accuracy. Thus, we evaluated the predictive value of a binary score simply based on the combination of these US features, regardless of the specific predictive value of each US feature, against the outcome of suspected malignancy at cytological diagnosis (TIR3 to TIR5 categories by SIAPEC-IAP [TIR+]). 1009 thyroid nodules from 1081 patients were considered. The US features of suspicion of all nodules were categorized in 5 binary scores (U1 to U5), each including from 1 to 5 of those features. U2 (at least 2 US suspicious features) was the most balanced predictor of TIR+ (PPV 0.48, NPV 0.93, LR+ 3.05 and LR- 0.24). Weighting the predictivity of the single features did not improve the estimate. Using U2 as the criterion to send nodules to FNAC would have reduced the number of biopsies by 60 % (604 patients) and the false negatives would have only accounted for 41 cases out of 237 TIR+ (17 %) with 39 cases of TIR3 and 2 cases of TIR4, including only 6 malignant nodules on histological examination. U2 performed much better than the ATA recommendations for detecting those nodules, resulting in TIR+ at cytology. This simple and reproducible sonographic score based on 2 US features of suspicion of malignancy has quite a good performance with respect to identifying thyroid lesions categorized by cytology as medium-high risk of malignancy and could allow us to reduce cytology costs for low-risk nodules.


Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS.
In cats, infection with T-lymphotropic retroviruses can cause T-cell proliferation and leukemia or T-cell depletion and immunosuppression. In humans, some highly T4 tropic retroviruses called HTLV-I can cause T-cell proliferation and leukemia. The subgroup HTLV-II also induces T-cell proliferation in vitro, but its role in disease is unclear. Viruses of a third subgroup of human T-lymphotropic retroviruses, collectively designated HTLV-III, have been isolated from cultured cells of 48 patients with acquired immunodeficiency syndrome (AIDS). The biological properties of HTLV-III and immunological analyses of its proteins show that this virus is a member of the HTLV family, and that it is more closely related to HTLV-II than to HTLV-I. Serum samples from 88 percent of patients with AIDS and from 79 percent of homosexual men with signs and symptoms that frequently precede AIDS, but from less than 1 percent of heterosexual subjects, have antibodies reactive against antigens of HTLV-III. The major immune reactivity appears to be directed against p41, the presumed envelope antigen of the virus.


Wavelet unfolded partial least squares for near-infrared spectral quantitative analysis of blood and tobacco powder samples.
Continuous wavelet transform (CWT) has been shown to be a high-performance signal processing technique in multivariate calibration. However, the signal processed by CWT with a specific wavelet may account for only a part of the information. To effectively utilize more abundant information contained in analytical signals, a method, named as wavelet unfolded partial least squares (WUPLS), was proposed. In the approach, the measured dataset is firstly extended by CWT with different wavelets, and then partial least squares (PLS) is employed to develop the quantitative model between the extended dataset and the target values. In order to select the representative wavelets, principal component analysis (PCA) is used to investigate the distribution of the signals obtained by CWT with different wavelets. The performance of the method was tested with blood and tobacco powder samples. Compared with the results obtained by PLS methods, the WUPLS method combined with signal processing techniques is proven to be a promising tool for improving the near-infrared (NIR) spectral analysis of complex samples.


[Changes in the microcirculatory vessels of the human stomach in ulcer disease].
At the ulcerous disease certain alterations in the microcirculatory bed of all the gastric wall layers take place in the zone of the ulcer and in the areas adjoining the ulcerous focus. In the gastric wall areas, remote from the ulcer, the alterations in the microcirculatory bed are poorly manifested. The most essential deviations from the norm are defined in the mucosal tunic and in the gastric tela submucosa according to the ulcer localization. The disorders in the microcirculatory bed at the ulcerous disease affect the microarchitectonics, the wall structure and the size of the microvessel lumens and their contents. Maximal alterations are observed in capillaries and postcapillary-venular portion of the microcirculatory bed, which are manifested as a considerable dilatation of the microvessels mentioned, deformity, presence of rather great protrusions of their wall. The resistive vessels of the microcirculatory bed, at the ulcerous disease, suffer to a less extent. The morphometric data have stated certain decrease of their diameter when comparing to the norm. The adaptive apparatuses of the bloodflow regulation at the ulcerous disease are essentially altered, increasing number of the arteriolovenular anastomoses is noted in the gastric wall as compared to the norm.


Characterization of macroalgal-associated microbial communities from shallow to mesophotic depths at Manawai, Papahānaumokuākea Marine National Monument, Hawai'i.
The Papahānaumokuākea Marine National Monument, Hawai'i, is one of the most isolated and protected archipelagos in the world, making it a natural laboratory to examine macroalgal-microbial diversity because of limited direct anthropogenic impacts. We collected the most abundant macroalgae from nine sites ranging from shallow subtidal (1.5 m) to mesophotic (75 m) depths around Manawai (Pearl and Hermes Atoll). We characterized the macroalgal bacterial communities via high-throughput amplicon sequencing and compared the influence of host phylum, species, site, and depth on these relationships at a single atoll. Ochrophyta species had the lowest bacterial diversity compared to Chlorophyta and Rhodophyta. Site and/or depth may influence the microbial community structure associated with Microdictyon setchellianum, indicating a possible disconnect of these microbial communities among habitats. Chondria tumulosa, a cryptogenic species with invasive traits, differed in associated microbiota compared to the native Laurencia galtsoffii, an alga from the same family collected at the same site and depth. While there was overlap of bacterial communities across sites for some algal species, the majority had minimal macroalgal-microbial community connectivity across Manawai. This mesophotic system, therefore, did not appear to be refugia for shallow water coral reefs at microscopic scales. Additional studies are required to identify other significant influences on microbial community variation.


Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients.
The effects of hydroxyethylstarch (HES) 130/0.4 6% and gelatin 4% on inflammation, endothelial integrity, and renal function after cardiac surgery were compared. Sixty patients aged >80 yr undergoing cardiac surgery were randomized to receive gelatin (n=30) or HES 130/0.4 (n=30). The colloid was used in the priming of the cardiopulmonary bypass circuit (500 ml) and for volume replacement until the second postoperative day (POD). Serum creatinine, creatinine clearance, IL-6, IL-10, intercellular adhesion molecule-1 (sICAM-1), urinary glutathione transferase-alpha, and neutrophil gelatinase-associated lipocalin (NGAL) were measured perioperatively. Serum creatinine was also reported approximately 60 days after discharge. The mean(sd) volume of gelatin infused was 4180(440) ml, which was greater than the volume of HES infused 2910(330) ml (P=0.002). The mean(sd) volume of serum creatinine on the first POD was 151(24) micromol litre(-1) in the gelatin group and 126(13) micromol litre(-1) in the HES group (P=0.004). Values for the second POD were 161(0.26) and 133(16) micromol litre(-1), respectively (P=0.004). Creatinine clearance was lower in the gelatin group on the first POD [37(7) vs 46(8) ml min(-1) 1.73 m2 (P=0.004)] and the second POD [32(8) vs 45(10) ml min(-1) 1.73 m2 (P=0.002)]. Kidney function approximately 60 days after discharge did not differ between the groups. IL-6, IL-10, and sICAM-1 were significantly lower in the HES group than in the gelatin group on the first and second PODs. Urinary alpha-GST increased in both groups to a comparable extent. Urinary NGAL concentrations were higher in the gelatin than in the HES patients 5 h after surgery and on the first and second PODs. In cardiac surgery patients aged >80 years, volume therapy with HES 130/0.4 6% was associated with less marked changes in kidney function and a less marked endothelial inflammatory response than gelatin 4%.


Embolization of a cavernous carotid fistula through the vein of Labbé: a new alternative transvenous access route.
Endovascular treatment of carotid cavernous fistulas (CCFs) via a transvenous approach is standard, but in rare cases this approach is challenging due to absence or thrombosis of the commonly used venous routes. A 61-year-old woman presented with a symptomatic CCF with all but one of the venous access routes to the CCF thrombosed, leaving an engorged superficial middle cerebral vein (SMCV) as the only venous outflow from the cavernous sinus. Access to the CCF was made possible after careful navigation of the sigmoid sinus, the vein of Labbé and the SMCV, bypassing the need for surgical access to the SMCV or for a direct transorbital puncture. The CCF was completely occluded by coiling and Onyx embolization. The patient made an uneventful recovery, with resolution of her symptoms. To the best of our knowledge, this access route has not been previously reported in the treatment of CCFs.


Novel determination of filtration coefficient of ovine placenta and intramembranous pathway.
We recently reported that distilled water injected into the amniotic compartment is rapidly absorbed by the fetal blood, which perfuses the fetal membranes and the fetal surface of the placenta, i.e., by the "intramembranous pathway." In the present study, we infused warmed distilled water at 2 ml.min-1.kg estimated fetal wt-1 into the amniotic compartment for 6-8 h in 12 chronically catheterized sheep. A steady state was achieved in amniotic fluid, fetal blood, and maternal blood osmolalities in 5.1 +/- 0.3 (SE) h. During the steady state, all of the infused water must pass to the ewe. Because the amount of water directly crossing the fetal membranes into the maternal circulation was not significantly different from zero (3.3 +/- 5.8% of total), we assumed all water crossed the placenta. The placental filtration coefficient was then calculated during the steady state as the infusion rate divided by the changes in the transplacental osmotic gradient and averaged 0.0260 +/- 0.0055 ml.min-1.mmHg-1.kg fetal wt-1. Attempts to correct this value for placental reflection coefficients less than 1 were unsatisfactory; thus the uncorrected value appears to provide the best estimate of the placental filtration coefficient. Similar calculations yielded a value of 0.00137 +/- 0.00025 ml.min-1.mmHg-1.kg-1 for the filtration coefficient of the intramembranous pathway. Thus this method provides a relatively simple new technique for estimating the filtration coefficient of the ovine placenta and intramembranous pathway under steady-state conditions.


Effect of Ser392 phosphorylation on the structure and dynamics of the polybasic domain of ADP ribosylation factor nucleotide site opener protein: a molecular simulation study.
ADP ribosylation factor nucleotide site opener (ARNO) as a guanine nucleotide exchange factor (GEF) activates small GTPases called ADP ribosylation factors (Arfs), which function as molecular switches and regulate a variety of cell biological events. ARNO directly interacts with the transmembrane a2-subunit isoform of the proton-pumping vacuolar ATPase in an acidification-dependent manner, and this interaction plays a crucial role in the regulation of the protein degradation pathway. A recent study reported specific interactions of a2N with the ARNO375-400 peptide corresponding to the polybasic (PB) domain of ARNO, which is a crucial regulatory element in the autoregulation and modulation of Arf-GEF activity. Interestingly, phosphorylation of Ser392 completely abolishes this interaction, and the experimental structure shows significant structural rearrangements. To investigate the effect of Ser392 phosphorylation on the structure and dynamics of the ARNO375-400 peptide, we employed all atom molecular dynamics (MD) simulations of the phosphorylated and unphosphorylated PB domain of the ARNO protein. A Hamiltonian-based replica exchange method called biasing potential replica exchange MD was used to enhance conformational sampling. Simulations predicted that the isolated PB domain is highly flexible, with the C-terminal region of the unphosphorylated state being unstable. In contrast, Ser392 phosphorylation increases the overall stability of the peptide. In agreement with experimental results, our simulations further support the hypothesis that phosphorylation induces disorder to order transitions and provide new insights into the structural dynamics of the PB domain. Phosphorylation of Ser392 appears to stabilize the C-terminal α-helix via formation of salt bridges between phospho-Ser392 and Arg390, Lys395, and Lys396.


Anti-inflammatory and analgesic activities of the methanol leaf extract of Phyllanthus amarus in some laboratory animals.
Phyllanthus amarus is used in Nigeria and other parts of the world as a medicinal plant. The plant has a history of use in Ayurvedic medicine for over 2000 years as well as a wide variety of traditional applications. It is being evaluated for anti-inflammatory and analgesic potential because these phenomena have assumed a worldwide dimension as a result of their implications in a variety of diseases. The methanol extract of the leaves of P. amarus was investigated for its anti-inflammatory and analgesic activities in Wistar strain albino rats and mice using carrageenan-induced inflammation as well as histamine-induced edema. The analgesic effect was determined using acetic acid writhing method and formalin-induced paw lick test. Standard phytochemical analysis was carried out to determine the active constituents responsible for biological effects. The extract at 100 and 200 mg/kg reduced significantly (p<0.05) the formation of edema induced by histamine and carrageenan. In the acetic acid-induced writhing test, the extract showed good analgesic activity characterized by a significant reduction in the number of writhes with 100 and 200 mg/kg doses used when compared to the control group. In the formalin-induced paw lick test, the extract at 100 and 200 mg/kg doses exhibited good analgesic activity characterized by a significant reduction in the number of paw licks at both the early and the late phases of the induced pain when compared with the untreated control group. Ibuprofen at 10 mg/kg served as the reference drug in all these tests. Results suggested that methanol extract of the leaves of P. amarus has great anti-inflammatory and analgesic potential. These biological effects exhibited by the extract of this plant may be attributed to the presence of flavonoids and other phenols contained therein.


The effect of gamma-irradiation on the viability of Cryptosporidium parvum.
Cryptosporidium parvum is 1 of the major causative organisms in waterborne diarrheal illness. Not only does C. parvum spread ubiquitously in our environment, it is also highly resistant to harsh environmental conditions and disinfectants. Therefore, a control measure for this protozoon is urgently required. This study investigated the effect of gamma-irradiation, in the range of 1,000-50,000 Gy, on the viability of C. parvum oocysts. Oocyst viability was determined by a combined indirect immunofluorescence and nucleic acid staining and animal infectivity study. The proportion of viable oocysts estimated by nucleic acid staining ranged from 94.2 to 89.4% in the 0- to 10,000-Gy groups, whereas it was reduced significantly to 58.6 or 45.7% in the 25,000- or 50,000-Gy group, respectively, at 24 hr postirradiation. In an animal infectivity study, oocysts irradiated with less than 10,000 Gy induced infections in mice wherein there were low numbers of oocysts per gram of feces amounting to 8-10.8% of the values in control mice, whereas with 50,000 Gy-irradiated oocysts, no oocysts were produced in the mice. This study suggests that at least 50,000 Gy of gamma-irradiation is necessary for the complete elimination of oocyst infectivity in mice.


Unexpected specificity of interspecies cobamide transfer from Geobacter spp. to organohalide-respiring Dehalococcoides mccartyi strains.
Dehalococcoides mccartyi strains conserve energy from reductive dechlorination reactions catalyzed by corrinoid-dependent reductive dehalogenase enzyme systems. Dehalococcoides lacks the ability for de novo corrinoid synthesis, and pure cultures require the addition of cyanocobalamin (vitamin B(12)) for growth. In contrast, Geobacter lovleyi, which dechlorinates tetrachloroethene to cis-1,2-dichloroethene (cis-DCE), and the nondechlorinating species Geobacter sulfurreducens have complete sets of cobamide biosynthesis genes and produced 12.9 ± 2.4 and 24.2 ± 5.8 ng of extracellular cobamide per liter of culture suspension, respectively, during growth with acetate and fumarate in a completely synthetic medium. G. lovleyi-D. mccartyi strain BAV1 or strain FL2 cocultures provided evidence for interspecies corrinoid transfer, and cis-DCE was dechlorinated to vinyl chloride and ethene concomitant with Dehalococcoides growth. In contrast, negligible increase in Dehalococcoides 16S rRNA gene copies and insignificant dechlorination occurred in G. sulfurreducens-D. mccartyi strain BAV1 or strain FL2 cocultures. Apparently, G. lovleyi produces a cobamide that complements Dehalococcoides' nutritional requirements, whereas G. sulfurreducens does not. Interestingly, Dehalococcoides dechlorination activity and growth could be restored in G. sulfurreducens-Dehalococcoides cocultures by adding 10 μM 5',6'-dimethylbenzimidazole. Observations made with the G. sulfurreducens-Dehalococcoides cocultures suggest that the exchange of the lower ligand generated a cobalamin, which supported Dehalococcoides activity. These findings have implications for in situ bioremediation and suggest that the corrinoid metabolism of Dehalococcoides must be understood to faithfully predict, and possibly enhance, reductive dechlorination activities.


Connecting deterministic and stochastic metapopulation models.
In this paper, we study the relationship between certain stochastic and deterministic versions of Hanski's incidence function model and the spatially realistic Levins model. We show that the stochastic version can be well approximated in a certain sense by the deterministic version when the number of habitat patches is large, provided that the presence or absence of individuals in a given patch is influenced by a large number of other patches. Explicit bounds on the deviation between the stochastic and deterministic models are given.


Assessment of Hearing in Children with Cerebral Palsy.
The objective of this study is to identify the prevalence and nature of auditory analyzer pathology in children with different forms of infant cerebral palsy by recording otoacoustic emission and recording short latency brainstem auditory evoked potentials. The subject group consisted of 75 children, 40 (53%) males and 35 (47%) were females, ranging from 3 to 14 years of age with a confirmed diagnosis of cerebral palsy on the basis of a psycho-neurological hospital in Tashkent. (Uzbekistan). The examination of children was carried out by the following methods: clinical examination of patients (general and otorhinolaryngological) and functional research methods of the auditory analyzer. All children underwent acoustic impedancemetry, including tympanometry with determination of the type of tympanogram and acoustic reflex. The data obtained revealed a bilateral lesion of the peripheral part of the auditory analyzer. Beilateral sensorineural hearing loss was detected in 21 - I - II degree, in 12 - III degree and in 15 - IV degree. Marked changes in the main parameters of BAEP were detected in the study of the stem structures of the auditory analyzer in children with cerebral palsy. Thus, disorganization, configuration disturbances of the component composition (I, III, V) were noted. Thus, the study revealed a disorder of auditory function by sound-detecting type and justified the need for hearing correction in these children. Evaluation of auditory function made it possible to determine the level of auditory analyzer injury and localization of the process from the results of a complex, objective examination.


Pose Estimation of Ultrasound Probe Using CNN and RNN with Image Reconstruction Loss.
It is necessary to estimate the pose of the probe with high accuracy to reconstruct 3D ultrasound (US) images only from US image sequences scanned by a 1D-array probe. We propose the probe pose estimation method using Convolutional Neural Network (CNN) with training by image reconstruction loss. To calculate the image reconstruction loss, we use the image reconstruction network which consists of an encoder that extracts features from the two US images and a decoder that reconstructs the intermediate US image between the two images. CNN is trained to minimize the image reconstruction loss between the ground-truth image and the reconstructed image. Through experiments, we demonstrate that the proposed method exhibits efficient performance compared with the conventional methods.


[Changes in the oxidation-reduction potential of the rat brain during nembutal anesthesia].
The effect of the pentobarbital anaesthesia (40 mg/kg) on the potential of the cortical redox state (E) recorded by implanted platinum electrode was studied in male albino rats. A gradual decrease in the breathing frequency induced by pentobarbital was accompanied by a gradual reduction of the redox potential by 30-80 mV. During the episodes with intermittent breathing there were additional decreases in redox potential by 30-80 mV against the background of which some rhythmical oscillations could be observed (the amplitude up to 25-30 mV, periods in 5-15 sec). The obtained data suggest that pentobarbital anaesthesia heavily changes the redox state of the brain tissue and shifts the balance to reducing state. Oscillations in redox potential against the background of breathing interruptions seem to be the typical glycolytic oscillations.


The childhood obesity response in Florida: where do we stand?
Childhood obesity is a major public health problem that is the focus of many child health programs and policies throughout the nation. Florida in particular has high rates of childhood obesity and inconsistent policies to address the issue. This paper examines the scope and challenge of addressing the childhood obesity epidemic in Florida from the perspective of childhood obesity stakeholders. As part of a larger assessment of the health of Florida's children for the Florida Child Health and Healthcare Quality Chartbook, the authors conducted focus groups and interviews with stakeholders from private and public organizations. The stakeholders represented healthcare providers, state and local agencies, and community-based programs that address nutrition and physical activity education, access to healthcare, health screenings, and environmental and policy change related to preventing childhood obesity. Stakeholders identified best practices, challenges, barriers, and priorities for addressing childhood obesity. Multilevel approaches, emphasizing the family were identified as best practices, along with the need for environmental policy change. Funding and a need for data were identified as the biggest challenges, while overcoming barriers such as myths and misinformation and developing a unified obesity message were identified as motivators. The major findings indicate that, although positive progress is being made in specific communities, a coordinated and comprehensive response is needed. To create policy and normative change, a statewide, multilevel framework is needed with a unifying message to better target policymakers. The framework should include targeted efforts at all levels that include education, promotion and environmental policy change.


A new frontier in CO2 flux measurements using a highly portable DIAL laser system.
Volcanic CO2 emissions play a key role in the geological carbon cycle, and monitoring of volcanic CO2 fluxes helps to forecast eruptions. The quantification of CO2 fluxes is challenging due to rapid dilution of magmatic CO2 in CO2-rich ambient air and the diffuse nature of many emissions, leading to large uncertainties in the global magmatic CO2 flux inventory. Here, we report measurements using a new DIAL laser remote sensing system for volcanic CO2 (CO2DIAL). Two sites in the volcanic zone of Campi Flegrei (Italy) were scanned, yielding CO2 path-amount profiles used to compute fluxes. Our results reveal a relatively high CO2 flux from Campi Flegrei, consistent with an increasing trend. Unlike previous methods, the CO2DIAL is able to measure integrated CO2 path-amounts at distances up to 2000 m using virtually any solid surface as a reflector, whilst also being highly portable. This opens a new frontier in quantification of geological and anthropogenic CO2 fluxes.


Screening for osteoporosis in men: a systematic review for an American College of Physicians guideline.
Screening for low bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is the primary way to identify asymptomatic men who might benefit from osteoporosis treatment. Identifying men at risk for low BMD and fracture can help clinicians determine which men should be tested. To identify which asymptomatic men should receive DXA BMD testing, this systematic review evaluates 1) risk factors for osteoporotic fracture in men that may be mediated through low BMD and 2) the performance of non-DXA tests in identifying men with low BMD. Studies identified through the MEDLINE database (1990 to July 2007). Articles that assessed risk factors for osteoporotic fracture in men or evaluated a non-DXA screening test against a gold standard of DXA. Researchers performed independent dual abstractions for each article, determined performance characteristics of screening tests, and assessed the quality of included articles. A published meta-analysis of 167 studies evaluating risk factors for low BMD-related fracture in men and women found high-risk factors to be increased age (>70 years), low body weight (body mass index <20 to 25 kg/m2), weight loss (>10%), physical inactivity, prolonged corticosteroid use, and previous osteoporotic fracture. An additional 102 studies assessing 15 other proposed risk factors were reviewed; most had insufficient evidence in men to draw conclusions. Twenty diagnostic study articles were reviewed. At a T-score threshold of -1.0, calcaneal ultrasonography had a sensitivity of 75% and specificity of 66% for identifying DXA-determined osteoporosis (DXA T-score, -2.5). At a risk score threshold of -1, the Osteoporosis Self-Assessment Screening Tool had a sensitivity of 81% and specificity of 68% to identify DXA-determined osteoporosis. Data on other screening tests, including radiography, and bone geometry variables, were sparse. Key risk factors for low BMD-mediated fracture include increased age, low body weight, weight loss, physical inactivity, prolonged corticosteroid use, previous osteoporotic fracture, and androgen deprivation therapy. Non-DXA tests either are too insensitive or have insufficient data to reach conclusions.


[Abdominal metastases from signet cell carcinoma of the appendix vermiformis].
Signet cell carcinomas are often aggressive tumours. A patient with this tumour, originally located in the appendix, was diagnosed with peritoneal metastases. When she later got abdominal symptoms, computer axial tomography indicated large infiltrating tumour masses in the pelvis. However, when a laparotomy was performed, the only macroscopic tumour masses was localised to the ovaries (Krukenberg tumour). The surgical intervention gave the patient an improved quality of life, and most likely prolonged survival. We stress the importance of thinking of this possibility.


Role of GluK1 kainate receptors in seizures, epileptic discharges, and epileptogenesis.
Kainate receptors containing the GluK1 subunit have an impact on excitatory and inhibitory neurotransmission in brain regions, such as the amygdala and hippocampus, which are relevant to seizures and epilepsy. Here we used 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a potent and selective agonist of kainate receptors that include the GluK1 subunit, in conjunction with mice deficient in GluK1 and GluK2 kainate receptor subunits to assess the role of GluK1 kainate receptors in provoking seizures and in kindling epileptogenesis. We found that systemic ATPA, acting specifically via GluK1 kainate receptors, causes locomotor arrest and forelimb extension (a unique behavioral characteristic of GluK1 activation) and induces myoclonic behavioral seizures and electrographic seizure discharges in the BLA and hippocampus. In contrast, the proconvulsant activity of systemic AMPA, kainate, and pentylenetetrazol is not mediated by GluK1 kainate receptors, and deletion of these receptors does not elevate the threshold for seizures in the 6 Hz model. ATPA also specifically activates epileptiform discharges in BLA slices in vitro via GluK1 kainate receptors. Olfactory bulb kindling developed similarly in wild-type, GluK1, and GluK2 knock-out mice, demonstrating that GluK1 kainate receptors are not required for epileptogenesis or seizure expression in this model. We conclude that selective activation of kainate receptors containing the GluK1 subunit can trigger seizures, but these receptors are not necessary for seizure generation in models commonly used to identify therapeutic agents for the treatment of epilepsy.


Selective enhancement and suppression of frog gustatory responses to amino acids.
Properties of the receptor sites for L-amino acids in taste cells of the bullfrog (Rana catesbeiana) were examined by measuring the neural activities of the glossopharyngeal nerve under various conditions. (a) The frogs responded to 12 amino acids, but the responses to the amino acids varied with individual frogs under natural conditions. The frog tongues, however, exhibited similar responses after an alkaline treatment that removes Ca2+ from the tissue. The variation in the responses under natural conditions was apparently due to the variation in the amount of Ca2+ bound to the receptor membrane. (b) The responses to hydrophilic L-amino acids (glycine, L-alanine, L-serine, L-threonine, L-cysteine, and L-proline) were of a tonic type, but those to hydrophobic L-amino acids (L-valine, L-leucine, L-isoleucine, L-methionine, L-phenylalanine, and L-tyrptophan) were usually composed of both phasic and tonic components. (c) The properties of the tonic component were quite different from those of the phasic component: the tonic component was largely enhanced by the alkaline treatment and suppressed by the acidic treatment that increases binding of Ca2+ to the tissue. Also, the tonic component was suppressed by the presence of low concentrations of salts, or the action of pronase E, whereas the phasic component was unchanged under these conditions. These properties of the phasic component were quite similar to those of the response to hydrophobic substances such as quinine. These results suggest that the hydrophilic L-amino acids stimulate receptor protein(s) and that the hydrophobic L-amino acids stimulate both the receptor protein and a receptor site similar to that for quinine. (d) On the basis of the suppression of the responses to amino acids by salts, the mechanism of generation of the receptor potential is discussed.


[Mother-child treatment in psychiatry. I: Overview of experiences up to now].
Basing on the growing interest in the work with relatives of mentally ill people, psychiatric inpatient treatment of mentally ill mothers together with their infants or toddlers is described. The introductory overview gives an account of various international experiences with psychiatric inpatient treatment of mother and child, the conditions existing especially in England are described, and hints are given in respect of the need to adopt that treatment model.


Food Composition Databases: Does It Matter to Human Health?
Food provides humans with more than just energy and nutrients, addressing both vital needs and pleasure. Food habits are determined by a wide range of factors, from sensorial stimuli to beliefs and, once commanded by local and seasonal availability, are nowadays driven by marketing campaigns promoting unhealthy and non-sustainable foodstuffs. Top-down and bottom-up changes are transforming food systems, driven by policies on SDGs and by consumer's concerns about environmental and health impacts. Food quality, in terms of taste, safety, and nutritional value, is determined by its composition, described in food composition databases (FDBs). FDBs are then useful resources to agronomists, food and mechanical engineers, nutritionists, marketers, and others in their efforts to address at maximum human nutrient needs. In this work, we analyse some relevant food composition databases (viz., purpose, type of data, ease of access, regularity of updates), inspecting information on the health and environmental nexus, such as food origin, production mode as well as nutritional quality. The usefulness and limitations of food databases are discussed regarding what concerns sustainable diets, the food 'matrix effect', missing compounds, safe processing, and in guiding innovation in foods, as well as in shaping consumers' perceptions and food choices.


Lupus Nephritis: Animal Modeling of a Complex Disease Syndrome Pathology.
Nephritis as a result of autoimmunity is a common morbidity associated with Systemic Lupus Erythematosus (SLE). There is substantial clinical and industry interest in medicinal intervention in the SLE nephritic process; however, clinical trials to specifically treat lupus nephritis have not resulted in complete and sustained remission in all patients. Multiple mouse models have been used to investigate the pathologic interactions between autoimmune reactivity and SLE pathology. While several models bear a remarkable similarity to SLE-driven nephritis, there are limitations for each that can make the task of choosing the appropriate model for a particular aspect of SLE pathology challenging. This is not surprising given the variable and diverse nature of human disease. In many respects, features among murine strains mimic some (but never all) of the autoimmune and pathologic features of lupus patients. Although the diversity often limits universal conclusions relevant to pathogenesis, they provide insights into the complex process that result in phenotypic manifestations of nephritis. Thus nephritis represents a microcosm of systemic disease, with variable lesions and clinical features. In this review, we discuss some of the most commonly used models of lupus nephritis (LN) and immune-mediated glomerular damage examining their relative strengths and weaknesses, which may provide insight in the human condition.


Task deactivation reductions and atrophy within parietal default mode regions are overlapping but only weakly correlated in mild cognitive impairment.
Reduced task deactivation within regions of the default mode network (DMN) has been frequently reported in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). As task deactivation reductions become increasingly used in the study of early AD states, it is important to understand their relationship to atrophy. To address this issue, the present study compared task deactivation reductions during a lexical decision task and atrophy in aMCI, using a series of parallel voxel-wise and region-wise analyses of fMRI and structural data. Our results identified multiple regions within parietal cortex as convergence areas of task deactivation and atrophy in aMCI. Relationships between parietal regions showing overlapping task deactivation reductions and atrophy in aMCI were then explored. Regression analyses demonstrated minimal correlation between task deactivation reductions and either local or global atrophy in aMCI. In addition, a logistic regression model which combined task deactivation reductions and atrophy in parietal DMN regions showed higher classificatory accuracy of aMCI than separate task deactivation or atrophy models. Results suggest that task deactivation reductions and atrophy in parietal regions provide complementary rather than redundant information in aMCI. Future longitudinal studies will be required to assess the utility of combining task deactivation reductions and atrophy in the detection of early AD.


Transcription-associated mutational pressure in the Parvovirus B19 genome: Reactivated genomes contribute to the variability of viral populations.
In this study we used non-overlapping parts of the two long open reading frames coding for nonstructural (NS) and capsid (VP) proteins of all available sequences of the Parvovirus B19 subgenotype 1a genome and found out that the rates of A to G, C to T and A to T mutations are higher in the first long reading frame (NS) of the virus than in the second one (VP). This difference in mutational pressure directions for two parts of the same viral genome can be explained by the fact of transcription of just the first long reading frame during the lifelong latency in nonerythroid cells. Adenine deamination (producing A to G and A to T mutations) and cytosine deamination (producing C to T mutations) occur more frequently in transcriptional bubbles formed by DNA "plus" strand of the first open reading frame. These mutations can be inherited only in case of reactivation of the infectious virus due to the help of Adenovirus that allows latent Parvovirus B19 to start transcription of the second reading frame and then to replicate its genome by the rolling circle mechanism using the specific origin. Results of this study provide evidence that the genomes reactivated from latency make significant contributions to the variability of Parvovirus B19.


[(18)F]Fluoromethyl-PBR28 as a potential radiotracer for TSPO: preclinical comparison with [(11)C]PBR28 in a rat model of neuroinflammation.
To develop radiotracer for the translocator protein 18 kDa (TSPO) in vivo, N-(2-[(18)F]fluoromethoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([(18)F]1, [(18)F]fluoromethyl-PBR28) was prepared by incorporating of fluorine-18 into triazolium triflate-PBR28 precursor (7). The radiochemical yield of [(18)F]1 after HPLC purification was 35.8 ± 3.2% (n = 11, decay corrected). Radiotracer [(18)F]1 was found to be chemically stable when incubated in human serum for 4 h at 37 °C. Both aryloxyanilide analogs (1 and 2) behaved similarly in terms of lipophilicity and in vitro affinity for TSPO. Here, both radiotracers were directly compared in the same inflammatory rat to determine whether either radiotracer provides more promising in vivo TSPO binding. Uptake of [(18)F]1 in the inflammatory lesion was comparable to that of [(11)C]PBR28, and [(18)F]1 rapidly approached the highest target-to-background ratio at early imaging time (35 min postinjection versus 85 min postinjection for [(11)C]PBR28). These results suggest that [(18)F]1 is a promising radiotracer for imaging acute neuroinflammation in rat. In addition, our use of a triazolium triflate precursor for [(18)F]fluoromethyl ether group provides the convenient application for radiofluorination of radiotracer containing a methoxy group.


The association between presenteeism and engagement of National Health Service staff.
Although several studies have demonstrated a relationship between staff engagement and health and wellbeing, none has analysed the association with presenteeism in the National Health Service (NHS) context. Our aim is to determine whether there is a relationship between presenteeism and staff engagement. A hierarchical logistic multilevel modelling of cross-sectional data from the NHS staff survey (2009) was conducted. We controlled for a range of demographic and socioeconomic background variables, including ethnic group, gender, age and occupational group. The sample was 156,951 respondents across all 390 English NHS trusts, each providing a random sample of employees. Engagement was measured using three facets: motivation, advocacy and involvement, which were also used in a composite score. There was a low-to-moderate negative correlation between presenteeism and staff engagement: odds ratio 0.42 (95% confidence interval [CI] 0.42-0.43) for overall staff engagement and 0.53 (95% CI 0.52-0.54) for staff advocacy of the trust; 0.53 (95% CI 0.52-0.54) for motivation and 0.50 (95% CI 0.49-0.51) for involvement. Putting pressure on health-care staff to come to work when unwell is associated with poorer staff engagement with their jobs.


Cannabis use is associated with reduced prevalence of non-alcoholic fatty liver disease: A cross-sectional study.
Cannabis use is associated with reduced prevalence of obesity and diabetes mellitus (DM) in humans and mouse disease models. Obesity and DM are a well-established independent risk factor for non-alcoholic fatty liver disease (NAFLD), the most prevalent liver disease globally. The effects of cannabis use on NAFLD prevalence in humans remains ill-defined. Our objective is to determine the relationship between cannabis use and the prevalence of NAFLD in humans. We conducted a population-based case-control study of 5,950,391 patients using the 2014 Healthcare Cost and Utilization Project (HCUP), Nationwide Inpatient Survey (NIS) discharge records of patients 18 years and older. After identifying patients with NAFLD (1% of all patients), we next identified three exposure groups: non-cannabis users (98.04%), non-dependent cannabis users (1.74%), and dependent cannabis users (0.22%). We adjusted for potential demographics and patient related confounders and used multivariate logistic regression (SAS 9.4) to determine the odds of developing NAFLD with respects to cannabis use. Our findings revealed that cannabis users (dependent and non-dependent) showed significantly lower NAFLD prevalence compared to non-users (AOR: 0.82[0.76-0.88]; p<0.0001). The prevalence of NAFLD was 15% lower in non-dependent users (AOR: 0.85[0.79-0.92]; p<0.0001) and 52% lower in dependent users (AOR: 0.49[0.36-0.65]; p<0.0001). Among cannabis users, dependent patients had 43% significantly lower prevalence of NAFLD compared to non-dependent patients (AOR: 0.57[0.42-0.77]; p<0.0001). Our observations suggest that cannabis use is associated with lower prevalence of NAFLD in patients. These novel findings suggest additional molecular mechanistic studies to explore the potential role of cannabis use in NAFLD development.


Withdrawal of life sustaining treatment in children in the first year of life.
Since the enactment of the Texas Advance Directives Act of 1999, the Memorial Hermann Hospital Medical Appropriateness Review Committee (MARC) MARC reviewed six cases of children in the first year of life, three from the Neonatal ICU and three from the Pediatric ICU. We aimed to describe the characteristics of these patients and the role of the MARC in this process. A single reviewer retrospectively reviewed the cases for patient diagnoses, demographics, related ethical issues and the actions of the MARC. Each of the six patients required life-sustaining therapy, and each patient had a Do Not Resuscitate order on the chart. The MARC determined that it would be appropriate to withdraw life-sustaining support in four of the cases and to continue support in two of the cases. Five of the patients died in the hospital before discharge: two after discontinuation of support, one during the 10-day waiting period, and two died on full support after the Committee determined that continued treatment was medically appropriate. One patient was transferred to another hospital during the 10-day waiting period. These cases document the application of the TADA/MARC process in infants, even in circumstances where care was withdrawn without concurrence of the family. We found the MARC process to demand a very high degree of certainty of diagnosis and prognosis to determine continuation of care to be inappropriate. We conclude that the MARC promoted communication and provided additional protections to patients, families, physicians and staff.


Expression of the gonococcal global regulatory protein Fur and genes encompassing the Fur and iron regulon during in vitro and in vivo infection in women.
The ferric uptake regulatory protein, Fur, functions as a global regulatory protein of gene transcription in the mucosal pathogen Neisseria gonorrhoeae. We have shown previously that several N. gonorrhoeae Fur-repressed genes are expressed in vivo during mucosal gonococcal infection in men, which suggests that this organism infects in an iron-limited environment and that Fur is expressed under these conditions. In this study we have demonstrated expression of the gonococcal fur gene in vitro, in human cervical epithelial cells, and in specimens from female subjects with uncomplicated gonococcal infection. In vitro studies confirmed that the expression of the gonococcal fur gene was repressed during growth under iron-replete growth conditions but that a basal level of the protein was maintained. Using GFP transcriptional fusions constructed from specific Fur binding sequences within the fur promoter/operator region, we determined that this operator region was functional during N. gonorrhoeae infection of cervical epithelial cells. Furthermore, reverse transcription-PCR analysis, as well as microarray analysis, using a custom Neisseria Fur and iron regulon microarray revealed that several Fur- and iron-regulated genes were expressed during N. gonorrhoeae infection of cervical epithelial cells. Microarray analysis of specimens obtained from female subjects with uncomplicated gonococcal infection corroborated our in vitro findings and point toward a key role of gonococcal Fur- and iron-regulated genes in gonococcal disease.


Epidemiology and clonality of carbapenem-resistant Acinetobacter baumannii from an intensive care unit in Palermo, Italy.
Multidrug-resistant Acinetobacter baumannii, initially considered as having a poor clinical relevance, is frequently isolated from infection cases in intensive care units. We describe the epidemiology of carbapenem resistant A. baumannii (CRAB) in a general ICU in Palermo, Italy, from October 2010 to March 2011. 58 of 61 isolates exhibited MICs for meropenem or imipenem ≥16 mg/L. Forty-nine carried blaOXA-23 and two blaOXA-58 genes.Five subtype clusters were detected by rep-PCR. Clusters D and E included 10 isolates that tested negative for the carbapenem resistance genes. MLST attributed all isolates, but two, with sequence type (ST)2, whereas the two remaining isolates with ST78.The respiratory tract was the most common site of infection (26 out of 36 cases. 72.2%). A high infection related mortality rate was observed (18 out of 35 patients, 51.4%). Nineteen patients tested positive for other multidrug resistant organisms in addition to CRAB. In eight cases isolates belonging to distinct subtype clusters and/or with distinct carbapenemase profiles were identified. Carbapenem resistance was prominently driven by the dissemination of CRAB isolates belonging to ST2, carrying the carbapenemase gene blaOXA-23. The colonization/infection of some patients by multiple strains is suggestive of an endemic circulation of CRAB.


Protective efficacy of a virus-vectored multi-component vaccine against porcine reproductive and respiratory syndrome virus, porcine circovirus type 2 and swine influenza virus.
Porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2 (PCV2) and swine influenza virus (SIV) are three of the most economically important swine pathogens, causing immense economic losses to the global swine industry. Monovalent commercial vaccines against each of the three viruses are routinely used in pig farms worldwide. A trivalent vaccine against all three pathogens would greatly simplify the vaccination programme and reduce the financial burden to the swine industry. In this study, by using an attenuated strain of PRRSV (strain DS722) as a live virus vector, we generated a multi-component vaccine virus, DS722-SIV-PCV2, which expresses the protective antigens from SIV and PCV2. The DS722-SIV-PCV2 trivalent vaccine virus replicates well, and expresses PCV2 capsid and SIV HA proteins in vitro. A subsequent vaccination and challenge study in 48 pigs revealed that the DS722-SIV-PCV2-vaccinated pigs had significantly reduced lung lesions and viral RNA loads when challenged with PRRSV. Upon challenge with PCV2, the vaccinated pigs had partially reduced lymphoid lesions and viral DNA loads, and when challenged with SIV the vaccinated pigs had significantly reduced acute respiratory sign scores. The results from this study demonstrate the potential of DS722-SIV-PCV2 as a candidate trivalent vaccine, and also shed light on exploring PRRSV as a potential live virus vaccine vector.


Direct antigen presentation by DC shapes the functional CD8(+) T-cell repertoire against the nuclear self-antigen La-SSB.
Controversy still surrounds the importance of cross-presentation versus endogenous or direct presentation of MHC-I restricted Ag in CD8(+) T-cell (T(CD8+)) immunity. It is even less clear what relative role these pathways play in shaping the T-cell repertoire specific for ubiquitous self-antigens, especially in cases where both Ag presentation pathways could potentially be involved. Here we provide evidence that a T(CD8+) repertoire specific for a determinant from the nuclear autoantigen La-SSB is largely shaped by direct presentation. In this system, mouse T(CD8+) reactive to a xenogeneic human La (hLa(51-58)) K(b) peptide did not recognize directly presented peptide on either spleen cells from hLa-Tg mice or hLa transfected syngeneic cells. Interestingly, the same T(CD8+) were activated by in vivo challenge with allogeneic APC expressing either the Tg hLa or loaded with intact recombinant hLa protein, indicating functional cross-presentation of the hLa(51-58). However, in irradiated bone marrow chimeric mice, DC expressing Tg hLa, but not WT DC that matured in hLa-Tg mice, constitutively presented the hLa(51-58) to T(CD8+). These data demonstrate that although both the direct- and cross-presentation pathways are potentially operative in revealing hLa(51-58) to T(CD8+), the T(CD8+) repertoire to this determinant is shaped quantitatively according to the efficiency of Ag presentation.


Molecular Epidemiology of High-Risk Human Papillomavirus in High-Grade Cervical Intraepithelial Neoplasia and in Cervical Cancer in Parakou, Republic of Benin.
Human papilloma virus (HPV) infection remains a worldwide concern, especially in Sub-Saharan Africa where cervical cancer is the leading cause of cancer death in women. The aim of the study was to determine the prevalence and genotypic distribution of High-Risk HPV (HR-HPV) involved in Cervical Intraepithelial Neoplasia (CIN) II and III and in cervical cancer in Parakou. Out of a total of 149 samples of cervical tissues archived, fixed and paraffin-embedded, 78 samples with histological diagnosis of CIN-II, CIN-III and cervical cancer went through deparaffinization with xylene, followed by an extraction of HPV DNA and the detection of HR-HPV by real-time multiplex PCR. The average age of the women was 40.05±13.99 years. The samples were positive to at least one HR-HPV genotype in 76.92% (50/65) of cases. The HR-HPV genotypes which are most common in the cervical cancer and in CIN-II and III were, respectively HPV-39 (38 and 37.50%), HPV-18 (35 and 31.30%), HPV-45 (35 and 31.30%), HPV-35 (9 and 25%) and HPV-52 (9 and 12.50%). The HPV-16 was absent. This study helped to detect (in samples archived, fixed and paraffin-embedded tissues) HR-HPV involved in high-grade precancerous lesions and in cervical cancer in Parakou, some of which are not covered by currently available vaccines.


Effect of transcranial direct current stimulation of stroke patients on depression and quality of life.
[Purpose] The aim of this study was to assess the effects of transcranial direct current stimulation (tDCS) on depression and quality of life (QOL) in patients with stroke, by conducting conventional occupational therapy with and without tDCS on 20 patients each. [Subjects and Methods] The experimental group (N=20) received both tDCS and conventional occupational therapy, while the control group (N=20) received false tDCS and conventional occupational therapy. The treatment was conducted 20 times over a four-week period; each session was 30 minutes long. The Beck Depression Inventory (BDI) was administered to score the depression levels in patients before and after the intervention, while the stroke-specific quality of life (SS-QOL) was measured to compare the QOL. [Result] Following the intervention, the patients in the experimental group showed a significant decrease in depression and an increase in the QOL. In contrast, the control group showed no significant changes in depression or QOL. Our findings indicate that tDCS decreased depression while increasing QOL in patients with stroke. [Conclusion] In other words, our study confirmed that the application of tDCS during stroke rehabilitation improves the depression symptoms and QOL in patients.


[Differences in serotonin and dopamine metabolism in psychopathy and sluggish schizophrenia].
The studies established some differences in the serotonin metabolism in psychopaths and in patients with sluggish schizophrenia (261+/-9 ng/ml and 329+/-7 ng/ml of whole blood respectively). A comparison of the homovanilin acid content in the blood serum of patients in both groups (normals -62.1+/-9.3 ng/ml, psychopathic personalities -86.0+/-10.1 ng/ml, schizophrenic patients -34.5+/-8.6 ng/ml) points to a tendency towards an intensification of the dopamine metabolism in patients with psychopathy and a drop in the intensity of dopamine metabolism in schizophrenic patients.


Feeding Cells with a Novel "Trojan" Carrier: Citrate Nanoparticles.
In this work, the preparation of novel calcium citrate (CaCit) nanoparticles (NPs) has been disclosed and the use of these NPs as "Trojan" carriers has been demonstrated. The concentration ratio between calcium ions and citrate ions was optimized, yielding spherical NPs with size in the range of 100-200 nm. Additionally, a fluorescent dye, fluorescein isothiocyanate (FITC), was successfully encapsulated by the coprecipitation method. The products were characterized by thermogravimetric analysis and scanning electron microscopy. The cellular uptake was investigated by incubating the synthesized fluorescent-tagged NPs with human keratinocytes using a confocal microscope. The accumulation of the FITC in the cells suggested that the CaCit NPs can potentially be used as novel drug carriers.


A phase 1 trial of 8-chloro-adenosine in relapsed/refractory acute myeloid leukemia: An evaluation of safety and pharmacokinetics.
This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML). 8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m2 , the highest dose tested was 800 mg/m2 . The end points were toxicity, disease response, and PK/PD measurements. The predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose-dependency for the accumulation of 8-Cl-Ado. Two 8-Cl-Ado metabolites accumulated at similar levels to 8-Cl-Ado. Cellular PK in eight patients indicated accumulation of 8-Cl-ATP, which was associated with AML blast cytoreduction in peripheral blood. The authors determined the RP2D of 8-Cl-Ado to be 400 mg/m2 . Given the cardiac adverse events observed, patients require monitoring for arrhythmias and QT interval during infusion. Although peripheral blood cytoreduction was observed, responses were transient, suggesting combination strategies will be required.


Nonparaxial vector-field modeling of optical coherence tomography and interferometric synthetic aperture microscopy.
A large-aperture, electromagnetic model for coherent microscopy is presented and the inverse scattering problem is solved. Approximations to the model are developed for near-focus and far-from-focus operations. These approximations result in an image-reconstruction algorithm consistent with interferometric synthetic aperture microscopy (ISAM): this validates ISAM processing of optical-coherence-tomography and optical-coherence-microscopy data in a vectorial setting. Numerical simulations confirm that diffraction-limited resolution can be achieved outside the focal plane and that depth of focus is limited only by measurement noise and/or detector dynamic range. Furthermore, the model presented is suitable for the quantitative study of polarimetric coherent microscopy systems operating within the first Born approximation.


[Duodenal injuries in blunt epigastric trauma (author's transl)].
The diagnostic and therapeutic problems of duodenal rupture in blunt epigastric trauma are shown in the light of 5 observations. Patients with blunt epigastric trauma must be supervised clinically for at least 48 hours in order to recognize in good time injuries of the internal organs by the increasing symptoms of peritoneal irritation. During the operation all abdominal organs are inspected and, in the event of suspected duodenal rupture, particularly the retroperitoneal wall segments are searched since the intestine is often ruptured simultaneously at several sites. Duodenoscopy during the operation accelerates the surgical exploration and is an additional safety factor. As a rule, the duodenal rupture closes without complication within the first 24 hours after suturing, while discovered too late and treated incompletely it may lead to death under the clinical picture of retroperitoneal phlegmon with septic shock; even today the overall mortality is still about 20%.


Deep learning prediction of hospital readmissions for asthma and COPD.
Severe asthma and COPD exacerbations requiring hospitalization are linked to increased disease morbidity and healthcare costs. We sought to identify Electronic Health Record (EHR) features of severe asthma and COPD exacerbations and evaluate the performance of four machine learning (ML) and one deep learning (DL) model in predicting readmissions using EHR data. Observational study between September 30, 2012, and December 31, 2017, of patients hospitalized with asthma and COPD exacerbations. This study included 5,794 patients, 1,893 with asthma and 3,901 with COPD. Patients with asthma were predominantly female (n = 1288 [68%]), 35% were Black (n = 669), and 25% (n = 479) were Hispanic. Black (44 vs. 33%, p = 0.01) and Hispanic patients (30 vs. 24%, p = 0.02) were more likely to be readmitted for asthma. Similarly, patients with COPD readmissions included a large percentage of Blacks (18 vs. 10%, p < 0.01) and Hispanics (8 vs. 5%, p < 0.01). To identify patients at high risk of readmission index hospitalization data of a subset of 2,682 patients, 777 with asthma and 1,905 with COPD, was analyzed with four ML models, and one DL model. We found that multilayer perceptron, the DL method, had the best sensitivity and specificity compared to the four ML methods implemented in the same dataset. Multilayer perceptron, a deep learning method, had the best performance in predicting asthma and COPD readmissions, demonstrating that EHR and deep learning integration can improve high-risk patient detection.


A Clinical Perspective on Arsenic Exposure and Development of Atherosclerotic Cardiovascular Disease.
Cardiovascular risk has traditionally been defined by modifiable and non-modifiable risk factors, such as tobacco use, hyperlipidemia, and family history. However, chemicals and pollutants may also play a role in cardiovascular disease (CVD) risk. Arsenic is a naturally occurring element that is widely distributed in the Earth's crust. Inorganic arsenic (iAs) has been implicated in the pathogenesis of atherosclerosis, with chronic high-dose exposure to iAs (> 100 µg/L) being linked to CVD; however, whether low-to-moderate dose exposures of iAs (< 100 µg/L) are associated with the development of CVD is unclear. Due to limitations of the existing literature, it is difficult to define a threshold for iAs toxicity. Studies demonstrate that the effect of iAs on CVD is far more complex with influences from several factors, including diet, genetics, metabolism, and traditional risk factors such as hypertension and smoking. In this article, we review the existing data of low-to-moderate dose iAs exposure and its effect on CVD, along with highlighting the potential mechanisms of action.


Calcium modulates calmodulin/α-actinin 1 interaction with and agonist-dependent internalization of the adenosine A2A receptor.
Adenosine receptors are G protein-coupled receptors that sense extracellular adenosine to transmit intracellular signals. One of the four adenosine receptor subtypes, the adenosine A2A receptor (A2AR), has an exceptionally long intracellular C terminus (A2AR-ct) that mediates interactions with a large array of proteins, including calmodulin and α-actinin. Here, we aimed to ascertain the α-actinin 1/calmodulin interplay whilst binding to A2AR and the role of Ca2+ in this process. First, we studied the A2AR-α-actinin 1 interaction by means of native polyacrylamide gel electrophoresis, isothermal titration calorimetry, and surface plasmon resonance, using purified recombinant proteins. α-Actinin 1 binds the A2AR-ct through its distal calmodulin-like domain in a Ca2+-independent manner with a dissociation constant of 5-12μM, thus showing an ~100 times lower affinity compared to the A2AR-calmodulin/Ca2+ complex. Importantly, calmodulin displaced α-actinin 1 from the A2AR-ct in a Ca2+-dependent fashion, disrupting the A2AR-α-actinin 1 complex. Finally, we assessed the impact of Ca2+ on A2AR internalization in living cells, a function operated by the A2AR-α-actinin 1 complex. Interestingly, while Ca2+ influx did not affect constitutive A2AR endocytosis, it abolished agonist-dependent internalization. In addition, we demonstrated that the A2AR/α-actinin interaction plays a pivotal role in receptor internalization and function. Overall, our results suggest that the interplay of A2AR with calmodulin and α-actinin 1 is fine-tuned by Ca2+, a fact that might power agonist-mediated receptor internalization and function.


Traumatic lung cyst: case report and literature review.
A young male patient with traumatic lung cyst, a rare lesion of blunt chest trauma, is presented. Compression of an elastic thorax with narrowing or closure of the airway produces a bursting or shearing force that creates an intrapulmonary cavity. The cyst may be filled with blood and is often associated with pulmonary contusion. The diagnosis is one of exclusion, based on an awareness that lung cyst can develop after trauma. Chest computerized tomography, as in the case described, may be useful to further delineate the lesion. Patients with traumatic lung cyst should be watched for respiratory distress, but the clinical course is usually uncomplicated, and the lesion completely resolves in 2 to 4 months. There are two indications for surgical treatment: infection in the cavity that is unresponsive to a trial of appropriate antibiotic therapy, and a cavity that does not progressively become smaller. In the patient presented, lobectomy was done 9 days postinjury and the cyst removed, and his subsequent recovery was without problems.


Receptors, adenylate cyclase, depression, and lithium.
Although numerous studies have suggested that depression may be associated with a reduction in synaptic noradrenaline in the brain, direct beta-adrenergic receptor agonists have not been tested in the treatment of depression until recently. Moreover, newer theories of antidepressant action suggest that a reduction in beta-adrenergic receptor sensitivity is a better correlate of antidepressant treatment than noradrenaline turnover changes. It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta-2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. Plasma cyclic AMP before treatment with salbutamol rose 26% in response to salbutamol 0.25 mg iv. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to iv salbutamol declined over 60%. The beta-adrenergic adenylate cyclase remained subsensitive 4 days after cessation of salbutamol therapy. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. The plasma cyclic GMP response to subcutaneous epinephrine, suggested as a model for presynaptic alpha-noradrenergic mechanisms, is also partially inhibited by Li therapy. Since cyclic AMP and cyclic GMP may be viewed as balancing substances, their interaction may provide a mechanism for Li's dual clinical effects in mania and depression. It is important that in vivo techniques be developed for evaluating receptor changes. The plasma cyclic AMP response to adrenergic stimulation provides an in vivo measure of receptor function that can be useful in studying drug effects during the clinical treatment of humans.


Depression among couples in the United States in the context of intimate partner violence.
This paper examines the relationship between intimate partner violence and depression. A multicluster random household sample of U.S. couples was interviewed as part of a five-year national longitudinal study (response rate = 72%). Depression was assessed with the CES-D. The multivariate analyses for men showed that the odds of depression did not vary significantly by type of male-to-female (MF) or female-to-male (FM) aggression. Men who engaged in infrequent binge drinking, compared to those who never binged, were less likely to be depressed, as were men with greater collective efficacy. For women, the multivariate analysis, showed that FM aggression (psychological: minor and severe, and physical) was associated with a greater likelihood of depression. Exposure to parental violence was also associated with depression. Women may experience depression as the result of psychological and physical aggression even if they are the perpetrators of such aggression.


Two-component mixture cure rate model with spline estimated nonparametric components.
In some survival analysis of medical studies, there are often long-term survivors who can be considered as permanently cured. The goals in these studies are to estimate the noncured probability of the whole population and the hazard rate of the susceptible subpopulation. When covariates are present as often happens in practice, to understand covariate effects on the noncured probability and hazard rate is of equal importance. The existing methods are limited to parametric and semiparametric models. We propose a two-component mixture cure rate model with nonparametric forms for both the cure probability and the hazard rate function. Identifiability of the model is guaranteed by an additive assumption that allows no time-covariate interactions in the logarithm of hazard rate. Estimation is carried out by an expectation-maximization algorithm on maximizing a penalized likelihood. For inferential purpose, we apply the Louis formula to obtain point-wise confidence intervals for noncured probability and hazard rate. Asymptotic convergence rates of our function estimates are established. We then evaluate the proposed method by extensive simulations. We analyze the survival data from a melanoma study and find interesting patterns for this study.


Minimum 10-year follow-up of micro-arc oxidation coating on a cementless grit-blasted tapered-wedge stem of total hip arthroplasty: a multicentre study.
Recently, a femoral stem treated with grit-blasting and micro-arc oxidation (MAO) coating has commercialised but medium-term follow-up studies are lacking. The aim of this study was to report the outcome of a grit-blasted and MAO-coated femoral component designed as a straight, double-wedged, tapered stem with a rectangular cross-section with minimum 10 years follow-up. Between March 2006 and December 2008, 309 primary total hip arthroplasties using a grit-blasted and MAO-coated femoral component were performed by 3 experienced hip surgeons in 3 hospitals. At minimum 10 years after index THA, 299 hips were living, 10 hips were deceased, and 65 hips were lost to follow-up or had a follow-up period <10 years. Finally, 234 hips were enrolled in this study. Mean duration of clinical follow-up was 129.6 months. The mean Harris Hip Score was improved from 46.9 to 88.4 at the final follow-up. 4 hips were revised for 2 aseptic femoral loosening, 1 aseptic acetabular cup loosening and 1 late infection. 3 hips were revised for a periprosthetic femoral fracture requiring a femoral component revision. The average time to revision was 51.6 (range 0-148) months. Kaplan-Meier survivorship analysis with an end point of revision for any reason demonstrated a survival rate of 97.4% at 10 years. Survival was 98.7% with revision for aseptic loosening as the endpoint. The outcomes of a cementless grit-blasted and MAO-coated tapered-wedge stem of THA were excellent to satisfactory after a follow-up of at least 10 years.